IVF News

The latest report (the eighth since 1989) on worldwide availability and uptake of assisted reproductive technologies (ARTs) shows continued growth in demand and progress towards fewer embryo implantations. The study, produced by the International Committee for Monitoring Assisted Reproductive Technology (ICMART) is based on figures from 1563 clinics in 53 countries and compiles all available data for the year 2002 (the latest available).

From a macro perspective the data showed a 25 per cent increase in reported ART cases (partly attributable to improved data collection but also strongly suggestive of a significant growth in demand across the period).

The total number of reported cycles was slightly more than 600,000, resulting in almost a quarter of a million live births. Overall delivery rates were around 22.4 per cent for each conventional IVF aspiration and 21.2 per cent for each sperm injection (ICSI). The cumulative delivery rate per aspiration was 26 per cent, with a range from 14 to 39 (the US achieving the highest for a high availability nation at 37.5 per cent).

There was, however, a huge variation in availability with the extremes being Ecuador where only two cycles were performed for every million inhabitants and Israel where the figure reached 3,688 per million. The size of the difference between countries with better healthcare and availability led to Professor Jacques de Mouzon, leader of the study, to suggest that there may be a place for more 'low cost' ART with lower success rates but higher availability (thus reducing pressure on provides to implant multiple embryos during the small number of expensive cycles received).

While the proportion of twin pregnancies decreased from 26.5 per cent to 25.7 per cent, and triplets from 2.9 per cent to 2.5 per cent, Dr Tarlatzis, President of the International Federation of Fertility Societies, expressed concern at the 'continued high incidence of multiple pregnancy'. The report noted that multiple pregnancies saw more premature births (94.2 per cent of triplets compared to 13.5 per cent for singletons) and higher mortality (71.2 per 1,000 among triplets, compared to 10.7 for singletons).

A 47 per cent increase in the use of frozen embryo transfer cycles was seen as positive and indicative of a move away from multiple implantations. A substantial increase in demand for ICSI was less easily explained.

Professor Mouzon said of the new data that even though imperfect, the study 'gives data that can inform debate and decision-making on issues such as availability and the benefits and risks of this important medical
practice'.

 Amsterdam, The Netherlands: A new technique for transplanting the ovaries of women who have lost their fertility as a result of cancer treatment was outlined to the 25th annual conference of the European Society of Human Reproduction and Embryology today (Monday 29 June). Dr. Pascal Piver, manager of the IVF Centre at Limoges University Hospital, Limoges, France, described a new, two-step method of ovarian transplant that has produced excellent results in women whose ovaries have been frozen because of cancer treatment. He said that his team’s technique worked to restore ovarian function quickly and already one patient from his clinic had had a baby and another had become pregnant.

“On June 22, a baby girl was born to a mother who had been menopausal for two years as a result of treatment for sickle cell anaemia. After transplanting her own ovarian tissue she started ovulating in four months and became pregnant naturally six months after transplantation. Both mother and baby are doing well,” he said.

Dr. Piver and colleagues set out to tackle one of the biggest problems of ovarian transplantation: the low response to stimulation caused by insufficient vascularisation of the transplanted tissue.

“In order for a woman to become pregnant, the ovaries need to be responsive to the action of hormones that cause them to release eggs each month,” he explained. “If the blood supply to the ovaries is insufficient, this will not happen, even though the transplant may look as though it has been successful.”

To overcome this problem they carried out a two-stage procedure, first grafting small pieces of the frozen ovarian tissue in the ovarian and peritoneal areas three days before the real transplant. The first graft encourages the growth of blood vessels and paves the way for the ovary to become fully functioning in a shorter time scale than would be possible if all the tissue were to be transplanted at the same time.

The researchers have so far utilised this technique with two patients who had been treated for cancer and had their ovaries frozen. In addition to the first patient, treated for sickle cell anaemia, the second patient had been treated for periarteritis nodosa, an inflammation of medium-sized arteries, which become swollen and damaged from attack by rogue immune cells.

“She suffered menopause for eight and a half years before transplantation,” said Dr. Piver. “But after transplanting half of the frozen ovary, she recovered spontaneous ovulation in four months. Her right fallopian tube had been destroyed by the ovarian retrieval, and the function of the ovary and hence the chances of pregnancy are limited in time. Hence we decided to collect the highest number of eggs we could, and carry out an IVF procedure on this patient. 

“Six months after the operation, we transferred two blastocysts. A total of 22 oocytes were retrieved and produced 16 embryos, which in turn produced seven blastocysts. Unfortunately the first time round this patient developed an ectopic pregnancy, but she is now pregnant again.”

The technique was developed by Dr. Piver and his team, he told the conference. “This is the first time that a pregnancy has been obtained after a ten year gap between ovarian cryopreservation and grafting. We believe that it represents a considerable advance on the methods of ovarian transplantation used until now, not least because we are able to obtain large numbers of oocytes. We hope that it will enable more young patients who have been cured of cancer to regain their reproductive health and become pregnant with their own children,” he said.

 Amsterdam, The Netherlands: Transferring just one embryo at a time to a woman’s womb after embryos have undergone preimplantation genetic diagnosis (PGD) and freezing at the blastocyst stage has become a real option after researchers achieved pregnancy rates that were as good as those for blastocysts that had not had a cell removed for PGD before freezing. Their results mean that it will be possible to reduce the number of multiple pregnancies after PGD and the consequent complications associated with these pregnancies. 

The research was presented at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam and published online in Europe’s leading reproductive medicine journal, Human Reproduction, simultaneously today (Tuesday).

Dr Yacoub Khalaf, director of the assisted conception unit at Guy’s and St Thomas’ Hospital, London (UK), told the conference: “To the best of our knowledge, our study is the first to provide reassurance that a strategy of elective single embryo transfer in good prognosis patients seeking PGD, backed by an efficient PGD cryopreservation service, can result in pregnancy rates that are comparable to those for non-biopsied embryos that are frozen as part of conventional fertility treatment. These results should empower fertility centres to include PGD cycles for inherited genetic disorders in their efforts to reduce the multiple pregnancy rates after various forms of assisted conception treatment. Given the increasing number of PGD cycles performed each year, the advantage of widespread application of this policy would be considerable.”

Until now, fertility specialists have not applied a single embryo transfer policy to PGD for inherited genetic disorders because of concerns about how well biopsied embryos survive after freezing and thawing. “It was thought that the effect of the biopsy might reduce the embryos’ tolerance to freezing. This concern was not based on any scientific evidence, only on observations of low survival rates of biopsied frozen embryos,” said Dr Khalaf.

From January 2006 to July 2008 Dr Khalaf and his colleagues offered single embryo transfer together with freezing of surplus blastocysts to couples seeking PGD for single inherited genetic disorders such as cystic fibrosis. All the embryos were biopsied for the purposes of PGD on the third day after fertilisation, which is the time that they start to divide. Healthy embryos were cultured in the laboratory for a further two to three days to check that they were capable of reaching the next appropriate stage of development – the blastocyst stage. At this point, 32 couples who had two or more embryos that had successfully reached the blastocyst stage were offered the option of having one transferred to the womb and the rest frozen.

The researchers compared the pregnancy outcomes from a subsequent 32 frozen-thawed PGD cycles in these couples with the pregnancy outcomes from a control group of couples where 191 cycles of conventional IVF/ICSI were carried out using embryos that were frozen and thawed before implantation, but not biopsied at any stage. 

They found that the blastocyst survival rate after thawing was similar between the PGD and IVF/ICSI groups (87% versus 88% respectively). There was no significant difference in the implantation and clinical pregnancy rates (35% versus 29% and 34% versus 36% respectively). The overall ongoing pregnancy rate for all frozen cycles (PGD and IVF/ICSI) was 34%, which compares favourably with the UK national average for frozen cycles (currently 18% live birth rate per thaw).

When the same period was compared with the period before the single embryo transfer policy was introduced for PGD couples, the multiple pregnancy rate in the cycles of fresh PGD dropped from 36% to 10% with no reduction in pregnancy rates.

Dr Khalaf said: “This research suggests that responsible clinical decisions do not have to come at the expense of reducing effectiveness of treatment. You can be responsible and maintain the chances of success for your patients by good clinical judgment and using the appropriate techniques.

“For patients, this provides reassurance that a couple’s chance of having a healthy child is not reduced by replacing only one blastocyst and freezing the surplus ones. Those frozen blastocysts do have a very good chance of leading to a healthy pregnancy too, and, therefore, patients will not feel pressurised to have more than one embryo replaced (with the increased risk of multiple pregnancies) in order to make use of their biopsied, unaffected embryos for which, otherwise, they might have little use. Now, these frozen blastocysts offer them the chance of an additional healthy pregnancy without having to go through the whole treatment cycle again.”

The first author of the paper in Human Reproduction, Dr Tarek El-Toukhy, a consultant in reproductive medicine and PGD at the assisted conception unit at Guy’s and St Thomas’ Hospital, said: “This study represents a continuation of our efforts to advance IVF and PGD safety through single blastocyst transfer and embryo freezing.”

 Amsterdam, The Netherlands: Researchers have found evidence that chronic disease in either a mother or father can create unfavourable conditions in the womb that are associated with the development of polycystic ovarian syndrome (PCOS) in daughters. In another study, researchers found that brothers of women with PCOS and insulin resistance are themselves at greater risk of developing insulin resistance or diabetes, suggesting that factors associated with the condition can be passed down to sons as well as daughters.

The two studies were presented to the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam heard today (Tuesday). 

Associate Professor Michael Davies told a news briefing: “We already know from clinical studies of women with reproductive problems that foetal growth restriction is associated with the development of PCOS symptoms in daughters, and that problems during pregnancy and in the way the mother adapts to the metabolic challenge of pregnancy can indicate the future cardiovascular health of both the mother and the child. What we don’t know is whether giving birth to a daughter who later develops PCOS is associated with increased, long term cardiovascular disease risk in the mother. Nor do we know whether conditions underlying chronic disease in the father increases the risk of PCOS in the daughter.”

Prof Davies, co-director of the Research Centre for the Early Origins of Health and Disease at the University of Adelaide (Australia), looked at records for all female babies who were born and survived between 1973-1976 at The Queen Elizabeth Hospital in Adelaide. He and his colleagues interviewed the daughters to build up a picture of their health and any history of chronic disease in their parents. So far, 998 (63%) have responded, and Prof Davies reported preliminary data up to mid-1975 to the conference.

Sixty-two daughters (6.2% of the group) had a pre-existing diagnosis of PCOS. Mothers of these women tended to have elevated blood pressure during pregnancy. Daughters were nearly eight times as likely to have PCOS if their mothers had it, and they had a slightly higher risk if their mothers smoked during pregnancy. Mothers were 1.6 times as likely to have high blood pressure in later life if their daughters developed PCOS. If their fathers had heart disease or stroke, the daughters also had a higher risk of PCOS: double and three times the risk respectively. A history of diabetes in either parent was not significant. 

Prof Davies said: “These findings suggest a new pathway for the development of PCOS. We think that factors associated with the pre-existence of cardiovascular dysfunction in the mother or the father, and which operate during pregnancy, may create adverse conditions for the foetus, which alter the metabolic profile of offspring, leading to insulin resistance and reproductive consequences, such as PCOS, for daughters. A family history of diabetes is, therefore, not essential to observe an insulin resistance-related disease in offspring.”

He said it was still unclear exactly how the cardiovascular risk in the father affected the daughter. “We firstly need to consider the potential role of a common environment; for instance, that families with high levels of obesity (and therefore cardiovascular disease) will also tend to have heavy daughters who are thereby more likely to be affected by PCOS. However, the paternal effect that we saw was independent of the daughter’s weight, maternal age, socioeconomic status, maternal smoking, and country of birth, which suggests either a direct genetic effect on the daughter, or an effect of paternal genetic factors that are expressed during pregnancy.”

Dr Verena Mattle told the news briefing that her study was the first to show that brothers of women who had PCOS and insulin resistance were themselves more likely to develop insulin resistance or even diabetes or dyslipidaemia (a disruption in the levels of lipids (or fats) in the blood).

“Until now, it was not clear whether the male relatives of women with PCOS were at increased risk for the metabolic disorders associated with PCOS,” said Dr Mattle, who is chief resident at the University Clinic of Gynecological Endocrinology and Reproduction Medicine in Innsbruck (Austria).

Dr Mattle and her colleagues conducted oral glucose tolerance tests on 15 brothers of sisters with PCOS and insulin resistance (group 1). They also performed a serum analysis to determine lipid levels. As a control, nine brothers of sisters with PCOS but without insulin resistance were included in the study (group 2).

The researchers found that in the first group eight brothers showed an insulin resistance, one was diagnosed with diabetes and six had a normal glucose tolerance test. All nine affected brothers had a body mass index (BMI) between 19-31 kg/m2 and had elevated cholesterol and triglyceride levels. The six unaffected brothers had a BMI between 23-29, and none had high levels of cholesterol or triglycerides. In the second group, no insulin resistance was diagnosed. BMI was between 18-27 and two brothers had elevated cholesterol levels. Although there was a trend towards higher BMI in the first group, Dr Mattle said there was no statistically significant difference in BMIs between the two groups.

Dr Mattle said: “These results mean that we should pay attention to the health not only of women with PCOS but also to their brothers as they seem to have an increased risk for the medical problems that make up the metabolic syndrome, such as insulin resistance, diabetes and cardiovascular disease. Our findings are also in accordance with the hypothesis that not only is PCOS is a heritable disease, but that factors associated with it, such as insulin resistance, can be passed down to the next generation of either sex.”

She said that it could not be the case that the high BMI by itself could have caused the insulin resistance and diabetes in the affected brothers. “There must be a correlation between PCOS and insulin resistance because we could only find brothers with insulin resistance in the group that had sisters with PCOS and insulin resistance, but we couldn’t find brothers with insulin resistance in the group that had sisters with PCOS and no insulin resistance. It is known that about 50% of women with PCOS are insulin resistant and also that lean PCOS patients are insulin resistant. The BMI of insulin-resistant and non-resistant brothers were not statistically different.”

Dr Mattle and her colleagues are continuing to test brothers of women with PCOS for insulin resistance and lipid levels to collect more data from a larger group. “At this stage we would hesitate to say that a genetic inheritance is definitely playing a role in the increased risk of insulin resistance and other, related conditions in these brothers. We need to explore the possible effect of conditions in the womb and also the role of the environment. However, we think our data strongly support the view that brothers of women with PCOS and insulin resistance may have an increased risk of insulin resistance, diabetes and other, adverse metabolic conditions,” she concluded

 Amsterdam, The Netherlands: Women with cystic fibrosis can have fertility treatment to help them have babies without any long-term adverse effects on either themselves or their children, according to new research presented at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam today (Tuesday).

Until relatively recently, cystic fibrosis (CF) was a death sentence and most people with the disease died by the time they reached their teenage years. Now, this is no longer the case, and, thanks to better treatment of the condition, people live far longer and want to start their own families. But women with CF face a problem in addition to the effects of pregnancy on their health: CF itself can make them infertile.

In the first, long-running study to investigate and evaluate systematically the use of assisted reproductive technology (ART) in a group of infertile women with CF, researchers based at the Hôpital Cochin Saint Vincent de Paul in Paris (France) looked at 24 women between 1998 and 2008. After assessing their health, three women were discouraged from undergoing fertility treatment for medical reasons and six are still being assessed. However, the remaining 15 women all received fertility treatment.

Dr Sylvie Epelboin, a gynaecologist, obstetrician and co-ordinator of the Paris-based ART-CF disease network, who led the research, said: “Women with cystic fibrosis often have thick cervical mucus preventing them from becoming pregnant naturally. However, a pregnancy can be achieved by the use of intrauterine insemination (IUI) or in vitro fertilisation (IVF). Fertility treatment has to depend on the woman’s pulmonary and nutritional status, and there are ethical concerns about the welfare of the child whose mother might become severely ill, have to receive a lung transplant or die.”

All 15 women had partners without the CF gene mutation and, apart from failing to conceive, other indicators of fertility were normal. The women were aged between 24 and 36.

The doctors tried IUI first with the patients and 15 successful pregnancies were achieved using this method. One woman had IVF after IUI failed and she became pregnant after frozen embryo transfer. Another woman became pregnant after egg donation because her ovaries had failed. In total, there were 17 pregnancies in 13 of the 15 women, resulting in 12 live births, two ongoing pregnancies and three miscarriages.

All the women, apart from one, were able to give birth without a caesarean section, and although 50% of them had diabetes during pregnancy and there was a slight decline in lung function during the year of pregnancy, all the mothers have remained healthy. The babies were born on average at around 37 weeks, with only four babies having a low birth weight of less than 2500g (birth weights ranged from 1910-3500g). There were no babies with very low birth weights (less than 1500g). Five babies were breastfed. All children (seven girls and five boys), aged 10 years to one month, are healthy.

Dr Epelboin said: “The results of our study are good news for women with cystic fibrosis because they show that ART is a hopeful option for them and does not increase the risk of medical problems or death for either themselves or their children. Furthermore, the possibility of ART for this growing population of young adults with cystic fibrosis has a positive impact on their quality of life by satisfying their wish to become parents. These women had given mature consideration to their desire for a child and were fully supported by their families. All these considerations are equally true for infertile men with CF, who also require ART, usually via ICSI, to have children.”

However, she warned that it was important that a network of dedicated CF, ART and obstetrical teams should look after women with CF before, during and after pregnancy. The women’s general health should be carefully assessed and they should receive medical, genetic and ethical counselling before embarking on fertility treatment.

“Treatments inducing ovulation must be conducted with the goal of achieving a moderate response and a single pregnancy, and close monitoring for prenatal care is needed throughout the pregnancy. It is important for CF women to have singleton pregnancies because of the extra strain that a multiple pregnancy would place on the lungs and heart, for nutritional balance, and because of the additional risks of premature birth, which could be linked to abdominal efforts caused by coughing. In addition, a single birth is easier for these women to manage for post-natal care and medical follow-up.”

Diabetes and glucose intolerance occur frequently in people with CF, due to the worsening of their pancreatic disease. Some CF women have diabetes before pregnancy and so it needs to be under perfect control with insulin before they become pregnant. Other CF women can develop diabetes as a result of their pregnancy (gestational diabetes), and this also needs to be carefully controlled and monitored although it frequently disappears once the woman has given birth.

Together with Dr Dominique Hubert, a lung specialist and co-ordinator of the network, Dr Epelboin is setting up a long-term survey that follows the CF mothers, couples and children and compares them to women who require ART but who do not have a severe genetic disease. “We want to see how they fare with regards to ethical concerns about the welfare of the child growing up in a family where the mother has CF, and how the mother’s prospects or need for a transplant and her limited life expectancy affect the child and the family. It is only through such long-term monitoring that we can confirm our preliminary optimistic conclusions,” she said.

 Amsterdam, The Netherlands: Daily sex (or ejaculating daily) for seven days improves men’s sperm quality by reducing the amount of DNA damage, according to an Australian study presented today (Tuesday) to the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam.

Until now there has been no evidence-based consensus amongst fertility specialists as to whether or not men should refrain from sex for a few days before attempting to conceive with their partner, either spontaneously or via assisted reproduction.

Dr David Greening, an obstetrician and gynaecologist with sub specialist training in reproductive endocrinology and infertility at Sydney IVF, Wollongong, Australia, said: “All that we knew was that intercourse on the day of ovulation offered the highest chance of pregnancy, but we did not know what was the best advice for the period leading up to ovulation or egg retrieval for IVF.

“I thought that frequent ejaculation might be a physiological mechanism to improve sperm DNA damage, while maintaining semen levels within the normal, fertile range.”

To investigate this hypothesis, Dr Greening studied 118 men who had higher than normal sperm DNA damage as indicated by a DNA Fragmentation Index (DFI). Men who had a more than 15% of their sperm (DFI >15%) damaged were eligible for the trial. At Sydney IVF, sperm DNA damage is defined as less than 15% DFI for excellent quality sperm, 15-24% DFI for good, 25-29% DFI for fair and more than 29% DFI for poor quality; but other laboratories can have slightly different ranges.

The men were instructed to ejaculate daily for seven days, and no other treatment or lifestyle changes were suggested. Before they started, levels of DNA damage ranged between 15% and 98% DFI, with an average 34% DFI when measured after three days’ abstinence. When the men’s sperm was re-assessed on the seventh day, Dr Greening found that 96 men (81%) had an average 12% decrease in their sperm DNA damage, while 22 men (19%) and an average increase in damage of nearly 10%. The average for the whole group dropped to 26% DFI.

Dr Greening said: “Although the mean average was 26% which is in the ‘fair’ range for sperm quality, this included 18% of men whose sperm DNA damage increased as well as those whose DNA damage decreased. Amongst the men whose damage decreased, their average dropped by 12% to just under 23% DFI, which puts them in the ‘good’ range. Also, more men moved into the ‘good’ range and out of the ‘poor’ or ‘fair’ range. These changes were substantial and statistically highly significant. 

“In addition, we found that although frequent ejaculation decreased semen volume and sperm concentrations, it did not compromise sperm motility and, in fact, this rose slightly but significantly.

“Further research is required to see whether the improvement in these men’s sperm quality translates into better pregnancy rates, but other, previous studies have shown the relationship between sperm DNA damage and pregnancy rates.

“The optimal number of days of ejaculation might be more or less than seven days, but a week appears manageable and favourable. It seems safe to conclude that couples with relatively normal semen parameters should have sex daily for up to a week before the ovulation date. In the context of assisted reproduction, this simple treatment may assist in improving sperm quality and ultimately achieving a pregnancy. In addition, these results may mean that men play a greater role in infertility than previously suspected, and that ejaculatory frequency is important for improving sperm quality, especially as men age and during assisted reproduction cycles.”

Dr Greening said he thought the reason why sperm quality improved with frequent ejaculation was because the sperm had a shorter exposure in the testicular ducts and epididymis to reactive oxygen species – very small molecules, high levels of which can damage cells. “The remainder of the men who had an increase in DFI might have a different explanation for their sperm DNA damage,” he concluded.

 Amsterdam, The Netherlands: For the first time, researchers have been able to identify genetic predictors of the potential success or failure of IVF treatment in blood. Dr. Cathy Allen, from the Rotunda Hospital, Dublin, Ireland, told the 25th annual conference of the European Society of Human Reproduction and Embryology today (Wednesday 1 July) that her research would help understand why IVF works for some patients but not for others.

Previous work in this area has looked at gene profiles in such tissues as the uterine lining, but Dr. Allen and her team chose to examine the gene expression patterns in RNA extracted from peripheral (circulating) blood, an easily accessible biological sample. Blood samples were taken at eight different stages during the period around conception and the early stages of the IVF cycle. Five of these samples came from women who achieved clinical pregnancies, three from those who had implantation failure, and three from subfertile women who conceived spontaneously. Analysis showed that 128 genes showed a more than two-fold difference in expression in early clinical pregnancy compared with a non-pregnant state.

The molecular pathways that were most over-represented in this expression were concerned with angiogenesis (the growth of new blood vessels), endothelin signalling (blood vessel constriction), inflammation, oxidative stress (damage to cell structures), vascular endothelial growth factor (signalling processes in blood vessel growth), and pyruvate metabolism (the supply of energy to cells). “All these processes are important in the achievement and maintenance of pregnancy,” said Dr. Allen.

“We found that the gene expression profiles in blood of patients at the time of pituitary down-regulation showed interesting patterns of gene clustering. Over 200 genes were differentially expressed in patients who went on to achieve an IVF pregnancy compared with those who did not,” she said.

The researchers found that the peripheral blood gene expression ‘signature’ (also known as the transcriptome) before IVF was predictive of IVF outcome. This finding demonstrates the power of high-dimensional technology in biomarker discovery, and highlights the potential for developing clinically useful tools, they say. 

One of the most difficult decisions for patients who have had unsuccessful IVF treatments is whether they should undergo further attempts at IVF, or if there are ways to optimise chances of success. The researchers hope that the results generated by this work will lead to the development of a test to aid in IVF decision-making. They say that their work will help to identity biomarkers that can identify events occurring at implantation, the maintenance of pregnancy and successful or unsuccessful pregnancy outcome.

“IVF technology has advanced tremendously over the past three decades, yet success after IVF remains an unpredictable outcome,” said Dr. Allen. “Our work will help understand whether the implantation of embryos is influenced by the constantly changing expression of human genes.”

Previous studies in the field of gene-expression have focused on single genes as opposed to genome-wide screening of all the human genes with high density DNA microarrays, as used by Dr. Allen and her team. The advent of tools like microarrays that can simultaneously probe for up to 29,000 genes has radically changed scientific approaches to this type of research. “It’s like looking at how a team of players perform together rather than focusing on the individual players,” said Dr. Allen.

“We intend to look further at the most significant genes we have identified as being important in this field in order to be able to understand their exact biological role in reproductive function. We hope that our work will lead to the development of a clinically useful tool to help doctors counsel their patients in the difficult decision-making involved in IVF,” she said.

The 8th edition of the HFEA’s Code of Practice has now been published. It comes into force on 1st of October.

The 8th Code has been updated to reflect changes in the Human Fertilisation and Embryology Act 2008 and in HFEA policy. 

The Code is being published today to allow clinics time to familiarise themselves with the changes and update their policies and procedures as necessary in preparation for 1st October. 

Also published today:

• a guide to the Code, outlining what's changed
• revised and updated consent forms, including guidance
• new set of directions, replacing those issued previously
• a report on the consultation on the Code of Practice and consent forms

The Code is now easier to read and navigate and has achieved a Clear  English Standard from the Plain Language Commission for its guidance.

The HFEA is sending printed copies of the 8th Code to UK clinics and professional bodies.  Further copies of the Code and related documents and forms can be downloaded from the HFEA website.

Please note - the HFEA's 7th Code and all current directions etc will remain in force until 1st October.

UK scientists have created human sperm cells in the laboratory for the first time. The sperm, called in vitro-derived (IVD) sperm, were grown from embryonic stem (ES) cells. The researchers hope that the IVD sperm will provide a useful model for studying the development of sperm cells and the causes of male infertility.

The research team, from the North-East England Stem Cell Institute (NESCI) in Newcastle, UK, treated human ES cells with a chemical to prompt them into becoming germline stem cells ñ stem cells that are found in the reproductive organs and give rise to eggs and sperm. They then selected out these germline stem cells and continued to grow them in the presence of chemicals to encourage them to develop further into mature spem cells. The IVD sperm, like normal sperm, grew tails and were highly mobile. They also contained only 23 chromosomes, compared to the 46 chromosomes found in all other human cells (apart from egg cells which also contain only 23 chromosomes - when a sperm fertilises an egg they merge to form a single cell with a total of 46 chromosomes).

Professor Karim Nayernia, who led the study, said: ëThis is an important development as it will allow researchers to study in detail how sperm forms and lead to a better understanding of infertility in men ñ why it happens and what is causing it. This understanding could help us develop new ways to help couples suffering infertility so they can have a child which is genetically their own. It will also allow scientists to study how cells involved in reproduction are affected by toxins, for example, why young boys with leukaemia who undergo chemotherapy can become infertile for life ñ and possibly lead us to a solution'.

The research has sparked much controversy, however, with suggestions in the media that this work could lead to men becoming unnecessary for human reproduction. Professor Nayernia answered such claims, saying: ëWhile we can understand that some people may have concerns, this does not mean that humans can be produced ëin a dish' and we have no intention of doing this. This work is a way of investigating why some people are infertile and the reasons behind it. If we have a better understanding of what's going on it could lead to new ways of treating infertility.'

It is illegal to use IVD sperm for human reproduction in the UK. Laboratories can be granted a licence by the UK's Human Fertilisation and Embryology Authority (HFEA) to grow IVD sperm, and can use them to fertilise eggs, but the resulting embryos must be destroyed 14 days after fertilisation. The researchers are calling for the laws to be debated and reconsidered, as they feel that the technique has the potential to one day be used as a way for infertile men to father children. This would be a long way in the future, however, as much more would need to be known about the IVD sperm first and safety issues would need to be addressed. Previous studies in mice found that IVD sperm could be used to fertilise eggs but the resulting offspring had major health problems and died within five months, indicating an inherent defect in the IVD sperm.

The technique could only be performed using male ES cells that have an X and a Y chromosome. Female ES cells with two X chromosomes could not form mature sperm cells, because male genes found on the Y chromosome are essential for sperm development - further dispelling notions that the research could mean ëthe end of man'.

Other members of the scientific community have cast doubts on how significant this study of the creation of IVD sperm is. They have suggested that the data, published in the journal Stem Cells and Development, is insufficient to prove the IVD sperm are equivalent to normal sperm. Professor Azim Surani, from Cambridge University, believes they were ësperm-like cells' but ëa long way from being authentic sperm cells.'

Preimplantation genetic screening (PGS) for aneuploidy was first reported by Verlinsky et al (1995) and Munne et al (1995). Both of these initial studies analysed polar bodies. The aim of the technique is to help determine the best IVF embryo for transfer on the grounds of the polar body or embryo's chromosomes, by performing biopsy and analysis of the chromosomes using fluorescent in situ hybridisation (FISH). There have been hundreds of papers on the use of PGS. It is well known that for patients with advanced maternal age, there is an increased risk of chromosome abnormalities in the embryos they produce. Therefore this has been the main indication for PGS, but other indications include repeated IVF failure, repeated miscarriage (with normal karyotypes in the parents) and severe male factor infertility. As with many new technologies brought into the IVF clinic, there has been little evidence-based medicine to show that PGS increases delivery rates. At the late breaking news at the 2007 European Society of Human Reproduction and Embryology (ESHRE) annual meeting, Mastenbroek reported that their randomised controlled trial (RCT) on PGS showed that the treatment group had a lower delivery rate compared to the control group (Mastenbroek et al, 2007). Since then the debate about the validity of PGS has been rife. 

In 2007, as chair of the ESHRE PGD Consortium, I was asked if the Consortium steering committee could write a position statement on the use of PGS. The steering committee could not come to a consensus and so a position statement was never issued. The majority of the committee felt that further RCTs were required to convince the world whether PGS did or did not improve delivery rates (Harper et al, 2008). Since 2007, the British Fertility Society (BFS), the American Society for Reproductive Medicine (ASRM) and the American College of Obstetricians and Gynecologists (ACOG) have all issued statements that PGS should not be offered clinically. Several times at ESHRE 2009, I asked the audience how many were routinely performing PGS and many groups said they were.

There are now nine RCTs applied to both good (Staessens et al, 2008, Meyer et al, 2009, Jansen et al, 2008, Mersereau et al, 2008) and poor (Staessens et al, 2004, Stevens et al, 2004, Debrock et al, 2007, Hardarson et al, 2008, Mastenbroek et al, 2007) prognosis patients which have all shown that PGS has not improved the delivery rate, compared to a control group, and some of these studies show it has decreased the delivery rate. Almost all of these studies have been applied to cleavage stage embryos and FISH to study 5-12 chromosomes except Jansen et al (2008) who performed trophectoderm biopsy. Performing the biopsy at cleavage stages has a biological problem as this is the stage when human embryos show high levels of chromosome abnormalities (Harper et al, 1995, Munne et al, 1995) and so analysis of one cell from these embryos is not representative of the rest of the embryo. Many embryos are 'mosaic' - different cells may have different chromosomal complements - which may well self correct to give a normal embryo, but mosaicism creates a problem for PGS.

I reported the latest data of the ESHRE PGD Consortium at ESHRE 2009 in Amsterdam. The data shows that the majority of PGD cycles reported to the Consortium are for PGS (more than all of the other indications added together), but the latest data collection only includes cycles performed to the end of 2007, and so we have yet to see the 'Mastenbroek' effect. It will be interesting to see what the next data collection shows.

At the 2009 ESHRE meeting, I organised a post-congress course on the use of arrays in PGS. Several groups and companies reported on their development and clinical application of array CGH (comparative genomic hybridisation - which just looks at the chromosomes) or SNP arrays (single nucleotide polymorphism - which can look at the chromosomes and genes) for PGS. I summarised the session with three questions: 1) Are the arrays validated? 2) At what stage should we do the biopsy? 3) Have we done the necessary RCTs to determine if PGS will result in improved delivery rates? 

The arrays are being validated using a variety of single cells from normal and aneuploid cell lines and also polar bodies, blastomeres and trophectoderm cells. Cleavage stage biopsy is a good option for PGD for inherited disorders as it allows analysis of the paternal and maternal genes/chromosomes and a fresh transfer, but it may not be the optimal stage to biopsy for PGS (as described above). Therefore the third question needs to be answered by performing RCTs on either polar bodies (first and second) or trophectoderm. 

Also at the 2009 ESHRE conference, Professor Joep Geraedts, the

outgoing chairman, announced that ESHRE would be undertaking its first ever

clinical trial - a two stage study developed to assess the efficacy of PGS using polar body biopsy and analysis of 24 chromosomes using array technology. The first part of the study aims to determine if the technique of polar body biopsy and analysis of 24 chromosomes by array CGH is feasible. Two centres that have extensive polar body and PGS experience (Markus Montag, Hans van der Ven, University of Bonn, Germany and Cristina Magli and Luca Gianaroli, SISMER, Italy) are analysing the first and second polar bodies from a variety of patients who have agreed to be in the study. Any abnormal oocytes will also be examined to see whether the polar body abnormalities can really be used to predict that the oocyte will be abnormal. If the proof of principle part of the study is successful, the second part of the study will involve a multi centre RCT involving at least six centres in different EU countries, to determine if PGS gives an increased delivery rate in women of advanced maternal age. It was decided to run the trial on polar bodies as this will allow for a fresh transfer, the biopsy is less invasive and hopefully the results will be more reliable than cleavage or blastocyst biopsy as mosaicism will not affect the results. Dagan Wells (Oxford) is developing a blastocyst biopsy clinical trial for PGS with vitrification of the biopsied blastocysts to give time for the analysis. 

The UK's Human Fertilisation and Embryology Authority (HFEA) has reviewed the regulation of PGS and now no longer require clinics to offer PGS just for the criteria stated above (advanced maternal age, etc). Instead, they have placed the onus on clinics, requiring them to validate the use of PGS for each category of patient and to warn patients that PGS is an unproven technique in need of further research. If the RCTs show no improvement in delivery rates, it may be time to put PGS behind us, but if they show that PGS improves delivery rates this will be a major step forward for IVF treatment. We need to learn from the PGS experience to ensure that we rigorously test new techniques before we introduce them into clinical practice. 

References

1. Debrock S, Melotte C, Vermeesch J, et al. Preimplantation genetic screening (PGS) for aneuploidy in embryos after in vitro fertilization (IVF) does not improve reproductive outcome in women over 35: a prospective controlled randomized study. Fertil Steril 2007; 88:S237.

2. Hardarson T, Hanson C, Lundin K, et al. Preimplantation genetic screening in women of advance maternal age decrease in clinical pregnancy rate: a randomized controlled trial. Human Reprod 2008; 23:2806-2812.

3. Harper JC, Coonen E, Handyside AH, et al. Mosaicism of autosomes and sex chromosomes in morphologically normal, monospermic preimplantation human embryos. Prenat Diagn 1995; 15:41-49.

4. Harper J. Sermon K, Geraedts J, et al. What next for preimplantation genetic screening? Hum Reprod 2008; 23:478-480.

5. Jansen RP, Bowman MC, de Boer KA, et al. What next for preimplantation screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy. Hum Reprod 2008; 23:1476-1478.

6. Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening.

N Engl J Med 2007; 357:9-17.

7. Mersereau JE, Pergament E, Zhang X, et al. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008;90:1287-9

8. Meyer, L, Klipstein, S, Hazlett, W et al. A prospective randomized controlled trial of preimplantation genetic screening in the "good prognosis" patient. Fertil Steril 2009; 91:1731-1738.

9. MunnÈ S, Sultan KM, Weier HU, et al. Assessment of numeric abnormalities of X, Y, 18, and 16 chromosomes in preimplantation human embryos before transfer. Am J Obstet Gynecol. 1995;172(4 Pt 1):1191-9.

10. Staessen C, Platteau P, Van Assche E, et al. Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advance maternal age: a prospective randomize controlled trial. Hum Reprod 2004; 19:2849-2858.

11. Staessen C, Verpoest W, Donoso P, et al. Preimplantation genetic screening does not improve delivery rate in women under the age of 36 following single-embryo transfer. Hum Reprod 2008; 23:2818-2825.

12. Stevens J, Wale P, Surrey ES, Schoolcraft WB. Is aneuploidy screening for patients aged 35 or over beneficial? A prospective randomized trial. Fertil Steril 2004; 82(Suppl. 2):249

12. Verlinsky, Y, Cieslak, J, Freidine,M et al. Pregnancies following pre-conception diagnosis of common aneuploidies by fluorescent in-situ hybridization. Mol Hum Reprod 1995;1:265-269.